Salt forms and crystal forms of pyrazole-substituted imidazo[1,2-a]quinoxaline derivatives

Abstract

Provided are salt forms, crystal forms, and preparation methods of pyrazole-substituted imidazo[1,2-a]quinoxaline derivatives, specifically the salt forms, crystal forms, and preparation methods of the compound of formula (I), and their use in preparing drugs related to dual inhibitors of spleen tyrosine kinase (Syk) and vascular endothelial growth factor 2 (VEGFR2). #imgabs0#

Description

[0001] Cross-reference to related applications:

[0002] This application claims priority to patent application No. CN202110151592.7 filed on February 3, 2021, entitled “Salt forms and crystal forms of pyrazole-substituted imidazo[1,2-a]quinoxaline derivatives,” the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to a salt form, a crystal form and a preparation method of a pyrazole-substituted imidazo[1,2-a]quinoxaline derivative. Background Art

[0004] Spleen tyrosine kinase (Syk) is an intracellular tyrosine protein kinase and a member of the ZAP70 protein kinase family. Syk plays a critical role in the early development of B cells, lymphocyte ontogeny, and the function of mature B cells. During this process, it participates in multiple signal transduction pathways and exerts its effects without phosphorylation by Src kinase. In addition to being ubiquitously expressed in hematopoietic stem cells, Syk is also expressed in non-hematopoietic cells such as epithelial cells, hepatocytes, fibroblasts, neurons, and breast tissue, where it has diverse functions. Dysfunction of Syk PTK is implicated in numerous human diseases, including allergic reactions, asthma, inflammation, and autoimmune disorders. Numerous studies have shown that Syk is a key mediator of acute and chronic inflammation.

[0005] VEGFR2, also known as KDR or Flk-1, has been identified as a receptor for VEGF and VEGFC. It is an early marker of endothelial cell progenitors, and its expression is restricted to endothelial cells in vivo. VEGFR2 has been shown to be a major signal transducer in angiogenesis and the development of pathological conditions such as cancer and diabetic retinopathy. Studies have shown that anti-VEGF can inhibit the expression and activation of proinflammatory cytokines, thereby reducing ocular surface inflammation. VEGFR2 transduces the primary signal for angiogenesis through its potent tyrosine kinase activity. However, unlike other representative tyrosine kinase receptors, VEGFR2 does not use the Ras pathway as its primary downstream signaling pathway, but instead utilizes the phospholipase C-protein kinase C pathway to activate mitogen-activated protein (MAP) kinases and DNA synthesis. Therefore, inhibiting VEGFR2 activity and its downstream signaling is an important target for the treatment of diseases involving angiogenesis and inflammation.

[0006] Therefore, inhibition of Syk and VEGFR-2 activity can be used to treat allergic diseases, autoimmune diseases and inflammatory diseases, including but not limited to dry eye and allergic conjunctivitis, retinal inflammatory diseases, age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP), cancer, rheumatoid arthritis, glomerulonephritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDs) and asthma. Summary of the Invention

[0007] The present invention provides a crystal form A of a compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 16.76±0.20°, 17.55±0.20°, and 21.84±0.20°.

[0008]

[0009] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 15.36±0.20°, 16.76±0.20°, 17.55±0.20°, 21.84±0.20°, 23.49±0.20°, and 24.42±0.20°.

[0010] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 15.36±0.20°, 16.76±0.20°, 17.55±0.20°, 21.25±0.20°, 21.84±0.20°, 23.49±0.20°, 24.42±0.20°, 28.37±0.20°, and 30.15±0.20°.

[0011] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 16.76±0.20°, and may also have characteristic diffraction peaks at 15.36±0.20°, and / or 17.55±0.20°, and / or 21.25±0.20°, and / or 21.84±0.20°, and / or 23.49±0.20°, and / or 24.42±0.20°, and / or 28.37±0.20°, and / or 30.15±0.20°.

[0012] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form A using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96°, 14.14°, 15.36°, 16.21°, 16.76°, 17.55°, 17.96°, 21.25°, 21.84°, 23.49°, 24.42°, 28.37°, and 30.15°.

[0013] In some embodiments of the present invention, the XRPD pattern of the above-mentioned crystal form A is as follows: Figure 1 shown.

[0014] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned crystal form A are shown in Table 1 below:

[0015] Table 1 XRPD diffraction data of the crystal form A of compound of formula (I)

[0016] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 9.60 1.50 11 21.84 7.63 2 11.96 100.00 12 22.32 2.00 3 14.14 18.69 13 23.49 5.06 4 15.36 4.01 14 24.42 5.07 5 16.21 3.44 15 25.20 1.54 6 16.76 26.46 16 26.34 0.86 7 17.55 11.61 17 27.36 0.59 8 17.96 6.62 18 28.37 4.50 9 18.47 1.81 19 29.17 2.47 10 21.25 5.50 20 30.15 4.09

[0017] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows an endothermic peak at 332.4°C±3°C.

[0018] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form A shows endothermic peaks at 283.7°C±3°C and 332.4°C±3°C.

[0019] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form A is as follows: Figure 2 shown.

[0020] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned crystal form A shows a weight loss of 2.41±0.20% at 250.0°C±3°C.

[0021] In some embodiments of the present invention, the TGA spectrum of the above-mentioned A crystal form is as follows Figure 3 shown.

[0022] The present invention also provides a crystal form B of the compound of formula (I), wherein the X-ray powder diffraction pattern of the crystal form B using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 12.14±0.20°, 19.52±0.20°, 22.08±0.20°, and 28.22±0.20°.

[0023]

[0024] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.35±0.20°, 12.14±0.20°, 14.69±0.20°, 18.26±0.20°, 19.52±0.20°, 22.08±0.20°, and 28.21±0.20°.

[0025] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned B crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.35±0.20°, 12.14±0.20°, 14.69±0.20°, 16.70±0.20°, 18.26±0.20°, 19.52±0.20°, 22.08±0.20°, 26.55±0.20°, 27.31±0.20°, and 28.21±0.20°.

[0026] In some embodiments of the present invention, the XRPD pattern of the above-mentioned B crystal form is as follows: Figure 4 shown.

[0027] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned Form B are shown in Table 2 below:

[0028] Table 2 XRPD diffraction data of the crystal form B of compound of formula (I)

[0029] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 11.35 18.38 7 22.08 100.00 2 12.14 74.61 8 24.46 1.94 3 14.69 17.61 9 26.55 5.98 4 16.70 19.27 10 27.31 3.28 5 18.26 23.72 11 28.22 23.88 6 19.52 23.69 / / /

[0030] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned Form B shows an endothermic peak at 331.8±3°C.

[0031] In some embodiments of the present invention, the DSC spectrum of the above-mentioned B crystal form is as follows Figure 5 shown.

[0032] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned Form B shows a weight loss of 4.11±0.20% at 300.0°C±3°C.

[0033] In some embodiments of the present invention, the TGA spectrum of the above-mentioned B crystal form is as follows Figure 6shown.

[0034] The present invention also provides a method for preparing crystal form B, comprising the following steps:

[0035] (a) adding the crystalline form A of the compound of formula (I) to dimethylacetamide and dissolving it;

[0036] (b) placing the open glass vial containing the compound solution in a glass bottle pre-filled with acetone;

[0037] (c) Seal and subject to gas-liquid permeation at 20-30°C for three days;

[0038] (d) removing the supernatant with a pipette, and drying the remaining solid in an open air at room temperature for five days to obtain a solid;

[0039] (e) The solid was placed in a covered aluminum crucible and slowly heated to 150°C under a dry nitrogen atmosphere;

[0040] (f) Cool down to 20-30℃.

[0041] The present invention also provides a pharmaceutically acceptable salt of the compound of formula (I), characterized in that the pharmaceutically acceptable salt is a hydrate, a maleate or a gentisate.

[0042]

[0043] In some embodiments of the present invention, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrate, a maleate or a gentisate, and its structure is represented by formula (II), formula (III) or formula (IV).

[0044]

[0045] Among them, m is selected from 3.0 to 5.0, n is selected from 0.7 to 1.3, and p is selected from 0.7 to 1.3.

[0046] In some embodiments of the present invention, the above m is selected from 3.0, 3.5, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0; n is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3; p is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3.

[0047] In some embodiments of the present invention, the compound of formula (II), formula (III) or formula (IV) is selected from:

[0048]

[0049] The present invention also provides a crystal form C of the compound of formula (II-1), wherein the X-ray powder diffraction pattern of the crystal form C using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.53±0.20°, 12.05±0.20°, and 13.05±0.20°.

[0050]

[0051] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.53±0.20°, 12.05±0.20°, 13.05±0.20°, 20.87±0.20°, and 24.02±0.20°.

[0052] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned C crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.53°, 12.05°, 13.05°, 14.84°, 17.89°, 20.87°, 24.02°, and 26.84°.

[0053] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned crystal form C is as follows: Figure 7 shown.

[0054] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned crystal form C are shown in Table 3 below:

[0055] Table 3 XRPD diffraction data of the crystal form C of compound of formula (II-1)

[0056] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 6.53 100.00 11 20.87 3.31 2 12.05 5.83 12 21.22 0.88 3 13.05 33.09 13 21.95 0.58 4 14.39 0.62 14 23.15 0.75 5 14.84 1.66 15 24.02 3.12 6 15.48 0.44 16 24.87 0.50 7 16.34 0.73 17 26.84 1.34 8 17.14 0.51 18 28.44 0.62 9 17.89 1.45 19 29.78 0.27 10 19.14 0.39 20 32.93 0.20

[0057] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned crystal form C shows endothermic peaks at 58.8±3°C and 331.4±3°C.

[0058] In some embodiments of the present invention, the DSC spectrum of the above-mentioned crystal form C is as follows Figure 8 shown.

[0059] The present invention also provides a method for preparing crystal form C, comprising the following steps:

[0060] (a) dissolving the crystalline form A of the compound of formula (I) in tetrahydrofuran and water (volume ratio of 4:1);

[0061] (b) filtration through a polytetrafluoroethylene membrane;

[0062] (c) slowly evaporating the filtrate at 20-30° C. for 3 days to evaporate the solvent to dryness to obtain a solid;

[0063] The present invention also provides a D crystal form of the compound of formula (III-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.26±0.20°, 11.99±0.20°, 12.72±0.20°, and 14.52±0.20°.

[0064]

[0065] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.26±0.20°, 10.06±0.20°, 11.99±0.20°, 12.72±0.20°, 14.52±0.20°, 16.17±0.20°, and 20.23±0.20°.

[0066] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.26±0.20°, 10.06±0.20°, 11.99±0.20°, 12.72±0.20°, 14.52±0.20°, 16.17±0.20°, 16.75±0.20°, 20.23±0.20°, 20.83±0.20°, and 24.09±0.20°.

[0067] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned D crystal form is as follows: Figure 9 shown.

[0068] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned D crystal form are shown in Table 4 below:

[0069] Table 4 XRPD diffraction data of the crystal form D of compound of formula (III-1)

[0070] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 7.26 92.65 6 16.17 25.28 2 10.06 16.92 7 16.75 16.75 3 11.99 88.18 8 20.23 32.56 4 12.72 100.00 9 20.83 11.64 5 14.52 58.74 10 24.09 15.46

[0071] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned D crystal form shows endothermic peaks at 72.0±3°C, 136.0±3°C and 207.0±3°C.

[0072] In some embodiments of the present invention, the DSC spectrum of the above-mentioned D crystal form is as follows Figure 10 shown.

[0073] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned D crystal form shows a weight loss of 4.73±0.20% at 150.0°C±3°C.

[0074] In some embodiments of the present invention, the TGA spectrum of the above-mentioned D crystal form is as follows Figure 11 shown.

[0075] In some embodiments of the present invention, the above-mentioned D crystal form 1 H NMR spectrum Figure 12 shown.

[0076] The present invention also provides the E crystal form of the compound of formula (IV-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 12.20±0.20°, 18.73±0.20°, 22.20±0.20°, 24.10±0.20°, and 24.58±0.20°.

[0077]

[0078] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.47±0.20°, 12.20±0.20°, 13.72±0.20°, 18.73±0.20°, 22.20±0.20°, 24.10±0.20°, 24.58±0.20°, and 27.62±0.20°.

[0079] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.47±0.20°, 10.61±0.20°, 12.20±0.20°, 13.72±0.20°, 14.99±0.20°, 18.73±0.20°, 19.53±0.20°, 20.83±0.20°, 22.20±0.20°, 24.10±0.20°, 24.58±0.20°, and 27.62±0.20°.

[0080] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned E crystal form is as follows: Figure 13 shown.

[0081] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned E crystal form are shown in Table 5 below:

[0082] Table 5 XRPD diffraction data of the crystal form E of compound of formula (IV-1)

[0083] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 7.47 51.52 8 20.83 24.53 2 10.61 18.87 9 22.20 100.00 3 12.20 58.82 10 23.02 19.49 4 13.72 28.41 11 24.10 66.49 5 14.99 24.52 12 24.58 48.32 6 18.73 81.31 13 27.62 32.52 7 19.53 22.15 14 28.35 18.41

[0084] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned E crystal form shows an endothermic peak at 291.4±3°C.

[0085] In some embodiments of the present invention, the differential scanning calorimetry (DSC) curve of the above-mentioned E crystal form shows endothermic peaks at 97.2±3°C and 291.4±3°C.

[0086] In some embodiments of the present invention, the DSC spectrum of the above-mentioned E crystal form is as follows Figure 14 shown.

[0087] In some embodiments of the present invention, the thermogravimetric analysis (TGA) curve of the above-mentioned E crystal form shows a weight loss of 6.72±0.20% at 150.0°C±3°C.

[0088] In some embodiments of the present invention, the TGA spectrum of the above-mentioned E crystal form is as follows Figure 15 shown.

[0089] In some embodiments of the present invention, the above-mentioned E crystal form 1 H NMR spectrum Figure 16 shown.

[0090] The present invention also provides a pharmaceutically acceptable salt of the compound of formula (I), characterized in that the pharmaceutically acceptable salt is hydrochloride, sulfate, phosphate, p-toluenesulfonate or hydrobromide.

[0091]

[0092] In some embodiments of the present invention, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride, sulfate, phosphate, p-toluenesulfonate or hydrobromide, and its structure is represented by formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX).

[0093]

[0094] Among them, p is selected from 0.7 to 2.3, q is selected from 0.7 to 1.3, r is selected from 0.7 to 2.3, s is selected from 0.7 to 1.3, and t is selected from 0.7 to 2.3.

[0095] In some embodiments of the present invention, p is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3; q is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3; r is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1. 3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3; s is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3; t is selected from 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3.

[0096] In some embodiments of the present invention, the compound of formula (V), formula (VI), formula (VII), formula (VIII) or formula (IX) has a structure represented by formula (V-1), formula (V-2), formula (VI-1), formula (VII-1), formula (VII-2), formula (VIII-1), formula (IX-1) or formula (IX-2),

[0097]

[0098]

[0099] The present invention also provides a crystal form F of the compound of formula (V-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.94±0.20°, 15.42±0.20°, and 16.71±0.20°.

[0100] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 9.42°, 11.94°, 14.11°, 15.42°, and 16.71°.

[0101] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned F crystal form is as follows: Figure 17 shown.

[0102] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned F crystal form are shown in Table 6 below:

[0103] Table 6 XRPD diffraction data of the crystal form F of the compound of formula (V-1)

[0104] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 9.42 8.28 4 15.42 27.54 2 11.94 100.00 5 16.71 20.52 3 14.11 18.06 / / /

[0105] The present invention also provides a G crystal form of the compound of formula (V-2), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 7.08±0.20°, 7.94±0.20°, 12.59±0.20°, 20.35±0.20°, and 26.35±0.20°.

[0106] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 7.08±0.20°, 7.94±0.20°, 12.59±0.20°, 13.55±0.20°, 15.59±0.20°, 16.90±0.20°, 20.35±0.20°, and 26.35±0.20°.

[0107] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.77°, 7.08°, 7.94°, 11.80°, 12.59°, 13.55°, 15.59°, 16.90°, 17.74°, 20.35°, 22.66°, and 26.35°.

[0108] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned G crystal form is as follows: Figure 18 shown.

[0109] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned G crystal form are shown in Table 7 below:

[0110] Table 7 XRPD diffraction data of the crystal form G of the compound of formula (V-2)

[0111] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 6.77 86.90 7 15.59 50.56

[0112] 2 7.08 93.23 8 16.90 42.68 3 7.94 86.93 9 17.74 21.97 4 11.80 26.48 10 20.35 84.11 5 12.59 100.00 11 22.66 29.21 6 13.55 43.40 12 26.35 61.38

[0113] The present invention also provides an H crystal form of the compound of formula (VI-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 12.83±0.20°, 20.25±0.20°, and 20.95±0.20°.

[0114] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 12.83±0.20°, 13.45±0.20°, 16.75±0.20°, 20.25±0.20°, 20.95±0.20°, 24.02±0.20°, and 24.45±0.20°.

[0115] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96°, 12.83°, 13.45°, 16.75°, 18.04°, 20.25°, 20.95°, 23.39°, 24.02°, and 24.45°.

[0116] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned H crystal form is as follows: Figure 19 shown.

[0117] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned H crystal form are shown in Table 8 below:

[0118] Table 8 XRPD diffraction data of Form H of Compound (VI-1)

[0119] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 11.96 81.80 6 20.25 48.57 2 12.83 100.00 7 20.95 47.43 3 13.45 30.83 8 23.39 14.30 4 16.75 35.78 9 24.02 26.75 5 18.04 33.00 10 24.45 32.89

[0120] The present invention also provides Form I of the compound of formula (VII-1), whose X-ray powder diffraction pattern with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.12±0.20°, 11.49±0.20°, 15.44±0.20°, 20.62±0.20°, and 21.98±0.20°.

[0121] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.12±0.20°, 11.49±0.20°, 15.44±0.20°, 18.58±0.20°, 20.62±0.20°, 21.98±0.20°, 22.98±0.20°, and 25.87±0.20°.

[0122] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned I crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 5.12±0.20°, 11.49±0.20°, 15.44±0.20°, 16.26±0.20°, 18.58±0.20°, 19.05±0.20°, 20.62±0.20°, 21.98±0.20°, 22.98±0.20°, 24.33±0.20°, 25.87±0.20°, and 27.23±0.20°.

[0123] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned Form I is as follows: Figure 20 shown.

[0124] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned Form I are shown in Table 9 below:

[0125] Table 9 XRPD diffraction data of the crystal form of compound I of formula (VII-1)

[0126] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength %

[0127] 1 5.12 81.30 8 21.98 30.71 2 11.49 100.00 9 22.98 11.86 3 15.44 37.76 10 24.33 13.73 4 16.26 7.29 11 25.87 30.19 5 18.58 18.17 12 27.23 11.30 6 19.05 12.59 13 31.12 8.12 7 20.62 70.68 / / /

[0128] The present invention also provides a J crystal form of the compound of formula (VII-2), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 13.24±0.20°, 24.70±0.20°, and 25.57±0.20°.

[0129] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 9.66±0.20°, 13.24±0.20°, 20.17±0.20°, 24.70±0.20°, and 25.57±0.20°.

[0130] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 9.66±0.20°, 13.24±0.20°, 14.53±0.20°, 16.06±0.20°, 18.90±0.20°, 20.17±0.20°, 24.70±0.20°, and 25.57±0.20°.

[0131] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned J crystal form is as follows: Figure 21 shown.

[0132] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned J crystal form are shown in Table 10 below:

[0133] Table 10 XRPD diffraction data of Form J of Compound (VII-2)

[0134] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 9.66 48.22 5 18.90 41.86 2 13.24 56.97 6 20.17 48.38 3 14.53 39.90 7 24.70 100.00 4 16.06 44.89 8 25.57 75.44

[0135] The present invention also provides a K crystal form of the compound of formula (VIII-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.89±0.20°, 9.78±0.20°, and 16.04±0.20°.

[0136] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.89°, 9.78°, 10.42°, 12.05°, 14.71°, and 16.04°.

[0137] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned K crystal form is as follows: Figure 22 shown.

[0138] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned K crystal form are shown in Table 11 below:

[0139] Table 11 XRPD diffraction data of crystal form K of compound of formula (VIII-1)

[0140] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 4.89 100.00 4 12.05 6.77 2 9.78 15.52 5 14.71 12.15

[0141] 3 10.42 7.38 6 16.04 14.57

[0142] The present invention also provides an L crystal form of the compound of formula (VIII-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 13.87±0.20°, and 18.52±0.20°.

[0143] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.62±0.20°, 13.87±0.20°, 18.52±0.20°, 19.17±0.20°, and 23.23±0.20°.

[0144] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 4.62°, 13.87°, 18.52°, 19.17°, 19.73°, 21.21°, 23.23°, 25.41°, 32.26°, and 34.34°.

[0145] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned L crystal form is as follows: Figure 23 As shown in 2V.

[0146] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the L crystal form are shown in Table 12 below:

[0147] Table 12 XRPD diffraction data of the crystal form L of the compound of formula (VIII-1)

[0148] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 4.62 100.00 6 21.21 4.90 2 13.87 16.24 7 23.23 7.11 3 18.52 23.87 8 25.41 5.35 4 19.17 11.36 9 32.26 2.03 5 19.73 5.09 10 34.34 3.03

[0149] The present invention also provides the M crystal form of the compound of formula (IX-1), whose Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 10.01±0.20°, 11.95±0.20°, and 23.57±0.20°.

[0150] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 10.01±0.20°, 11.95±0.20°, 14.12±0.20°, 16.72±0.20°, and 23.57±0.20°.

[0151] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 10.01°, 11.95°, 14.12°, 16.72°, 17.57°, 21.63°, and 23.57°.

[0152] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned M crystal form is as follows: Figure 24 shown.

[0153] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned M crystal form are shown in Table 13 below:

[0154] Table 13 XRPD diffraction data of the crystal form M of the compound of formula (IX-1)

[0155] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 10.01 81.98 5 17.57 33.42 2 11.95 100.00 6 21.63 38.31 3 14.12 26.73 7 23.57 39.58 4 16.72 39.24 / / /

[0156] The present invention also provides the N crystal form of the compound represented by formula (IX-2), whose X-ray powder diffraction pattern radiated by Cu Kα has characteristic diffraction peaks at the following 2θ angles: 11.95±0.20°, 17.68±0.20°, 23.87±0.20°, 26.47±0.20°, and 27.04±0.20°.

[0157] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned N crystal form using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.95±0.20°, 15.42±0.20°, 17.68±0.20°, 18.16±0.20°, 23.87±0.20°, 25.60±0.20°, 26.47±0.20°, and 27.04±0.20°.

[0158] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned N crystal form with Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 6.62±0.20°, 11.95±0.20°, 15.42±0.20°, 17.68±0.20°, 18.16±0.20°, 19.26±0.20°, 23.87±0.20°, 25.60±0.20°, 26.47±0.20°, 27.04±0.20°, and 28.33±0.20°.

[0159] In some embodiments of the present invention, the X-ray powder diffraction pattern of the above-mentioned N crystal form is as follows: Figure 25 shown.

[0160] In some embodiments of the present invention, the peak positions and relative intensities of the diffraction peaks in the Cu Kα radiation XRPD pattern of the above-mentioned N crystal form are shown in Table 14 below:

[0161] Table 14 XRPD diffraction data of Form N of the compound of formula (IX-2)

[0162] serial number Diffraction angle 2θ Relative strength % serial number Diffraction angle 2θ Relative strength % 1 6.62 26.46 7 23.87 50.14 2 11.95 67.45 8 25.60 27.42 3 15.42 46.12 9 26.47 100.00 4 17.68 60.08 10 27.04 62.82 5 18.16 35.97 11 28.33 23.28 6 19.26 20.31 / / /

[0163] The present invention also provides the use of the above-mentioned crystal form A, crystal form B, crystal form C, crystal form D or crystal form E in the preparation of drugs related to spleen tyrosine kinase (Syk) and vascular endothelial growth factor 2 (VEGFR2) dual inhibitors.

[0164] Technical Effects

[0165] The crystalline form of the compound of the present invention exhibits excellent inhibitory activity against both Syk and KDR (VEGFR-2) and possesses favorable pharmacokinetic properties, including favorable eye-to-blood ratios and tissue exposure. The salt and crystalline forms of the compound of the present invention are simple to prepare, and the crystalline form is stable and less susceptible to heat and light, facilitating formulation.

[0166] Definition and Description

[0167] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be construed as ambiguous or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient.

[0168] The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0169] The chemical reactions of the present invention are carried out in suitable solvents that are compatible with the chemical transformations of the present invention and the reagents and materials required. To obtain the compounds of the present invention, it may sometimes be necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0170] The present invention will be described in detail below through examples, which are not intended to limit the present invention in any way.

[0171] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0172] The present invention uses the following abbreviations:

[0173] ACN stands for acetonitrile; DMSO stands for dimethyl sulfoxide. N2: nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; ℃: degree Celsius; μm: micrometer; mm: millimeter; μL: microliter; moL / L: mole per liter; mg: milligram; s: second; nm: nanometer; MPa: megapascal; lux: lux; μw / cm 2 : microwatt per square centimeter; h: hour; Kg: kilogram; nM: nanomole, rpm: rotational speed; XRPD stands for X-ray powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis;1 H NMR stands for proton nuclear magnetic resonance.

[0174] The compounds of the present invention are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names, and all solvents used in the present invention are commercially available.

[0175] Instrument and analysis method of the present invention

[0176] 1.1 X-ray powder diffractometer (XRPD) method

[0177] Test method: Approximately 10 mg of sample was used for XRPD analysis.

[0178] Detailed XRPD instrument information and parameters are shown in Table 15 below:

[0179] Table 15 XRPD instrument information and parameters

[0180]

[0181]

[0182] 1.2 Differential Scanning Calorimeter (DSC)

[0183] Detailed DSC instrument information and test methods are shown in Table 16 below:

[0184] Table 16 DSC instrument information and test method

[0185]

[0186] 1.3 Thermogravimetric Analysis (TGA)

[0187] Detailed TGA instrument information and test methods are shown in Table 17 below:

[0188] Table 17 TGA instrument information and test method

[0189]

[0190] 1.4 High Performance Liquid Chromatography (HPLC)

[0191] High performance liquid chromatography detector (Agilent 1260 HPLC)

[0192] Column: Waters Xbridge C18, 150 × 4.6 mm, 5 μm

[0193] 12.2 Chromatographic conditions

[0194] Mobile phase A: 0.1% trifluoroacetic acid in water;

[0195] Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile;

[0196] Column temperature: 40°C;

[0197] Flow rate: 1 mL / min;

[0198] Detection wavelength: 254nm;

[0199] Injection volume: 10 μL;

[0200] Detection time: 10 minutes;

[0201] Diluent: ACN / H2O (4:1, vv)

[0202] The gradient program is shown in Table 18 below:

[0203] Table 18 HPLC gradient

[0204] Time (min) Mobile phase B (%) 0.0 5 6.0 80 8.0 80 8.1 5 BRIEF DESCRIPTION OF THE DRAWINGS

[0205] Figure 1 is the XRPD pattern of the crystalline form A of the compound of formula (I);

[0206] Figure 2 is the DSC spectrum of Form A of the compound of formula (I);

[0207] Figure 3 is the TGA spectrum of Form A of the compound of formula (I);

[0208] Figure 4 is the XRPD spectrum of Form B of the compound of formula (I);

[0209] Figure 5 is the DSC spectrum of Form B of the compound of formula (I);

[0210] Figure 6 is the TGA spectrum of Form B of the compound of formula (I);

[0211] Figure 7 is the XRPD spectrum of the crystalline form C of the compound of formula (II-1);

[0212] Figure 8 is the DSC spectrum of the crystal form C of the compound of formula (II-1);

[0213] Figure 9 is the XRPD spectrum of the D crystal form of the compound of formula (III-1);

[0214] Figure 10 is the DSC spectrum of the D form of the compound of formula (III-1);

[0215] Figure 11 This is the TGA spectrum of the D-form of the compound of formula (III-1);

[0216] Figure 12 The D crystal form of the compound of formula (III-1) 1 H NMR spectrum;

[0217] Figure 13 is the XRPD spectrum of Form E of the compound of formula (IV-1);

[0218] Figure 14 is the DSC spectrum of Form E of the compound of formula (IV-1);

[0219] Figure 15 This is the TGA spectrum of the E crystal form of the compound of formula (IV-1);

[0220] Figure 16 The E crystal form of the compound of formula (IV-1) 1 H NMR spectrum;

[0221] Figure 17 is the XRPD spectrum of Form F of the compound of formula (V-1);

[0222] Figure 18 is the XRPD spectrum of Form G of the compound of formula (V-2);

[0223] Figure 19 is the XRPD spectrum of the H crystal form of the compound of formula (VI-1);

[0224] Figure 20 is the XRPD spectrum of Form I of the compound of formula (VII-1);

[0225] Figure 21 is the XRPD spectrum of Form J of the compound of formula (VII-2);

[0226] Figure 22 is the XRPD spectrum of Form K of the compound of formula (VIII-1);

[0227] Figure 23 is the XRPD spectrum of the L-form of the compound of formula (VIII-1);

[0228] Figure 24is the XRPD spectrum of the M crystal form of the compound of formula (IX-1); and

[0229] Figure 25 This is the XRPD spectrum of the N-form of the compound of formula (IX-2). DETAILED DESCRIPTION

[0230] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0231] Preparation Example

[0232] Example 1: Preparation of Crystalline Form A of Compound (I)

[0233]

[0234] Step 1

[0235] First, 16L of dimethyl sulfoxide was added to a 50L reactor. Mechanical stirring was turned on at a speed of 150rpm and the temperature was displayed as an internal temperature of 15°C. Then 1950g of compound 1a, 1230g of 1H-imidazole-2-carboxylic acid methyl ester and 1880g of sodium carbonate were added in sequence, and heating was turned on, and the external heating temperature was set to 82°C. After stirring at an internal temperature of 78-80°C for 16 hours, the heating was turned off and the reaction solution was cooled to 30°C. The reaction solution was slowly poured into 30L of stirred water, and a large amount of yellow solid precipitated. Set the external temperature to 10°C, stir for 50 minutes, and the speed was 100rpm. Filtration was started, the internal temperature was displayed at 15°C, and the filtered solid was vacuum dried to obtain compound 1b.

[0236] 1 H NMR (400MHz, DMSO-d6) δppm 8.12 (d, J = 8.5 Hz, 1H), 8.04 (d, J = J = 2.0 Hz, 1H), 7.98-7.93 (m, 1H), 7.45 (s, 1H), 7.09 (s, 1H), 3.86 (s, 3H).

[0237] Step 2

[0238] First, 18L of ethanol and 4.5L of water were added to a 50L reactor. Stirring was started at 150rpm and the temperature displayed as an internal temperature of 15°C. Then 1665g of compound 1b, 1656g of thiourea dioxide and 859.5g of sodium bicarbonate were added in sequence. Heating was turned on and the external heating temperature was set to 65°C. When the internal temperature rose to 60-65°C, gas was released. Maintain this temperature for 1 hour, and when no more gas was released, the temperature was raised to 80°C. After stirring for 16 hours, heating was turned off and the reaction solution was cooled to 25°C. The reaction solution was slowly poured into 25L of stirred water in two batches, and a large amount of solid precipitated. Set the external temperature to 10°C, stir for 30 minutes, start filtering, the internal temperature displayed was 15°C, the precipitated solid was poured back into the kettle, stirring was turned on, 30L of water was added, heated to an internal temperature of 65°C, stirred for 16 hours, filtered while hot, and the filter cake was vacuum dried to obtain compound 1c.

[0239] 1 H NMR (400MHz, DMSO-d6) δppm 11.95 (s, 1H), 8.61 (d, J = 1.0 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 7.62-7.54 (m, 1H), 7.34-7.25 (m, 1H).

[0240] Step 3

[0241] After setting up the tail gas absorption device, add 13.5 L of 1,4-dioxane to a 50 L reactor. Start stirring at 150 rpm and set the internal temperature to 15°C. Turn on the heating, set the external heating temperature to 40°C, and then add 900 g of compound 1c and 825.98 g of N,N-dimethylaniline in sequence. Add 2610 g of phosphorus oxychloride dropwise using a constant pressure dropping funnel, maintaining the internal temperature between 35 and 40°C. After the addition is complete, stir at an internal temperature of 90-92°C for 16 hours, then turn off the heat and cool the reaction mixture to 25°C. Slowly pour the reaction mixture into 15 L of stirred water in batches. Set the external temperature to 30°C and stir for 1 hour. Slowly add 4 M aqueous sodium hydroxide solution at an internal temperature of 15-20°C to adjust the pH to 7. Heat to an internal temperature of 30°C, stir for an additional 30 minutes, filter, and vacuum dry the filter cake to yield compound 1d.

[0242] 1 H NMR (400MHz, DMSO-d6) δ=,9.01(s,1H),8.80(d,J=2.0Hz,1H),7.95(d,J=8.8Hz,1H),7.91(s,1H),7.84(dd,J=2.0,8.8Hz,1H).

[0243] Step 4

[0244] Add 9 L of dimethyl sulfoxide to a 50 L reactor at 20°C and start stirring at 150 rpm. Add 620.24 g of 4-morpholinoaniline, 1124.4 g of N,N-diisopropylethylamine, and 820.00 g of compound 1d in sequence. Stir at an internal temperature of 95-100°C for 24 hours. Turn off the heat and cool the reaction mixture to 25°C. Slowly pour the reaction mixture into 30 L of stirred water. Set the external temperature to 10°C, stir for 0.5 hours, filter, and return the filter cake to the reactor. Add 9 L of isopropanol to the reactor. Stir at an internal temperature of 82°C for 1 hour. Filter while hot, wash the filter cake with 2 L of hot isopropanol, and dry under vacuum at 40-50°C for 12 hours to obtain compound 1e.

[0245] 1 H NMR(400MHz,DMSO-d6)δppm 9.65(s,1H),8.74(d,J=1.0Hz,1H),8.48(s,1H),7.99(d,J=9.0Hz,2H),7. 59-7.55(m,2H),7.08-6.91(m,3H),3.78-3.72(m,4H),3.10-3.05(m,4H).

[0246] Step 5

[0247] Add 4 L of dimethyltetrahydrofuran to a 50 L reactor, start stirring at 150 rpm, and set the external temperature to 5°C. Then, add 500.00 g of 4-pyrazoleboronic acid pinacol ester and 333.00 g of N,N-diisopropylethylamine. Add 558.00 g of (2-(chloromethoxy)ethyl)trimethylsilane dropwise using a constant pressure dropping funnel at an internal temperature of 5-8°C. After the addition is complete, set the external temperature to 20°C and stir for 3 hours. Then, add 3.2 L of dimethyltetrahydrofuran, 1.8 L of water, 880.00 g of compound 1e, 640.00 g of potassium carbonate, and 85.00 g of 1,1-bis(diphenylphosphinoferrocenepalladium)dichloride to the reactor. Purge the reactor with nitrogen for 20 minutes, then set the external temperature to 85°C. Stir at an internal temperature of 80-82°C for 16 hours. Cool to an internal temperature of 20°C and add 2L of water and 15L of n-heptane to the reactor with stirring. Stir for 20 minutes, filter, and dry the filter cake to obtain 1200g of crude compound 1f. Add the crude compound 1f to a 50L reactor and add 12L of dimethyltetrahydrofuran. Turn on the heat and set the external temperature to 80°C. After the solid dissolves, add 360.00g of activated carbon and stir at an internal temperature of 80°C for 16 hours. Filter, cool the filtrate to 15-20°C, add 20L of n-heptane, stir at 15-20°C for 16 hours, filter, and vacuum dry the filter cake to obtain compound 1f.

[0248] Step 6

[0249] To a 50L reactor, add 7L of 1M tetrabutylammonium fluoride in tetrahydrofuran solution and start stirring at 150rpm. Add 700.00 grams of 1f and 77.69 grams of ethylenediamine in sequence. Set the external temperature to 72°C and stir at an internal temperature of 67°C for 16 hours. Continue to add 5.6L of tetrahydrofuran to the reactor, stir at an internal temperature of 40°C for 2 hours, 30°C for 2 hours, and 20°C for 16 hours. The reaction solution is filtered, and the filter cake is returned to the kettle and 10L of water and 5L of ethanol are added and stirred at an internal temperature of 60°C for 16 hours. Filter while hot and vacuum dry the filter cake to constant weight to obtain Form A of the compound of formula (I).

[0250] 1 H NMR(400MHz, DMSO-d6)δ:8.81(s,1H),8.43(s,1H),8.23(s,2H),7.92(d,J=8.8Hz,2H),7.80(s,1H),7.77-7.7 2(m,1H),7.71-7.63(m,1H),7.07(d,J=8.8Hz,2H),3.79-3.76(m,4H),3.16(br.s.,4H); MS(ESI)m / z:412[M+H] + .

[0251] Example 2: Preparation of Crystalline Form B of Compound (I)

[0252]

[0253] 19.1 mg of the crystalline Form A solid of Compound (I) was weighed and placed in a 3.0 mL glass vial. 0.5 mL of dimethylacetamide was added to dissolve the solid to obtain a clear solution. The 3.0 mL glass vial containing the clear solution was placed open in a 20 mL glass bottle pre-filled with 3 mL of acetone. After sealing, the vial was placed under room temperature for gas-liquid permeation for three days. The supernatant was aspirated with a pipette, and the remaining solid was left to dry open at room temperature for five days to obtain a solid. An appropriate amount of the solid was then weighed and placed in a covered aluminum crucible. The solid was heated from room temperature to 150°C at a rate of 10°C / min under the protection of 50 mL / min of dry nitrogen, and then cooled to room temperature. XRPD analysis revealed Form B of Compound (I).

[0254] Example 3: Preparation of Crystalline Form C of Compound (II-1)

[0255]

[0256] 20.1 mg of the crystalline Form A solid of Compound (I) was weighed and placed in a glass vial. 3.0 mL of tetrahydrofuran / water (4:1 volume ratio) was added to dissolve the solid. The sample solution was filtered through a 0.45 μm pore size polytetrafluoroethylene filter into a new 3.0 mL glass vial. The clear solution was slowly evaporated at room temperature for three days until the solvent evaporated to dryness, yielding a solid. XRPD analysis revealed Form C of Compound (II-1).

[0257] Example 4: Preparation of Crystalline Form D of Compound (III-1)

[0258]

[0259] 20.4 mg of Form A solid of Compound (I) was weighed and placed in a glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. 5.7 mg of maleic acid was added while magnetically stirring at room temperature (approximately 600 rpm) to obtain a milky white suspension. The suspension was then transferred to 50°C and magnetically stirred at approximately 700 rpm for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form D of Compound (III-1).

[0260] Example 5: Preparation of Crystalline Form E of Compound (IV-1)

[0261]

[0262] 18.4 mg of Form A solid of Compound (I) was weighed and placed in a glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. 7.5 mg of gentisic acid was added at room temperature with magnetic stirring (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred (approximately 700 rpm) for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form E of Compound (IV-1).

[0263] Example 6: Preparation of Crystalline Form F of Compound (V-1)

[0264]

[0265] 20.8 mg of Form A solid of Compound (I) was weighed and placed in a glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. The suspension was stirred magnetically at room temperature (approximately 600 rpm). 4.9 μL of concentrated hydrochloric acid was added to obtain a yellow suspension. The suspension was then stirred magnetically at 50°C (approximately 700 rpm) for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form F of Compound (V-1).

[0266] Example 7: Preparation of Crystalline Form G of Compound (V-2)

[0267]

[0268] 19.3 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of tetrahydrofuran / water (volume ratio 19:1) was added. The suspension was stirred magnetically at room temperature (approximately 600 rpm). 4.9 μL of hydrochloric acid was added to obtain a yellow suspension. The suspension was then stirred magnetically at 50°C (approximately 700 rpm) for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form G of Compound (V-2).

[0269] Example 8: Preparation of Crystal Form H of Compound (VI-1)

[0270]

[0271] 19.2 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. 12.2 μL of sulfuric acid was added while magnetically stirring at room temperature (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred at approximately 700 rpm for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form H of Compound (VI-1).

[0272] Example 9: Preparation of Crystalline Form I of Compound (VII-1)

[0273]

[0274] 22.5 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. 2.6 μL of phosphoric acid was added while magnetically stirring at room temperature (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred at approximately 700 rpm for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form I of Compound (VII-1).

[0275] Example 10: Preparation of Crystalline Form J of Compound (VII-2)

[0276]

[0277] 18.5 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of tetrahydrofuran / water (volume ratio 19:1) was added. 2.6 μL of phosphoric acid was added while magnetically stirring at room temperature (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred at approximately 700 rpm for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form J of Compound (VII-2).

[0278] Example 11: Preparation of Crystalline Form K of Compound (VIII-1)

[0279]

[0280] 21.3 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. 8.5 mg of p-toluenesulfonic acid was added while magnetically stirring at room temperature (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred at approximately 700 rpm for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form K of Compound (VIII-1).

[0281] Example 12: Preparation of Crystalline Form L of Compound (VIII-1)

[0282]

[0283] 18.6 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of tetrahydrofuran / water (volume ratio 19:1) was added. 8.3 mg of p-toluenesulfonic acid was added at room temperature with magnetic stirring (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred (approximately 700 rpm) for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form L of Compound (VIII-1).

[0284] Example 13: Preparation of Crystalline Form M of Compound (IX-1)

[0285]

[0286] 18.6 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of ethanol / dimethyl sulfoxide (volume ratio 19:1) was added. 9.9 mg of a 40% aqueous hydrobromic acid solution was added at room temperature with magnetic stirring (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred (approximately 700 rpm) for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form M of Compound (IX-1).

[0287] Example 14: Preparation of Crystal Form N of Compound of Formula (IX-2)

[0288]

[0289] 18.9 mg of Form A solid of Compound (I) was weighed and placed in an HPLC glass vial. 0.5 mL of tetrahydrofuran / water (volume ratio 19:1) was added. 9.8 mg of a 40% aqueous hydrobromic acid solution was added at room temperature with magnetic stirring (approximately 600 rpm) to obtain a yellow suspension. The suspension was then transferred to 50°C and magnetically stirred (approximately 700 rpm) for four days. After centrifugation, the solid was vacuum-dried at room temperature for two hours to obtain a solid. XRPD analysis revealed Form N of Compound (IX-2).

[0290] Characterization Examples

[0291] Example 1: Solid Stability Test of Crystalline Form A of Compound (I)

[0292] According to the "Guidelines for Stability Testing of APIs and Preparations" (Chinese Pharmacopoeia 2015 Edition, Part IV, General Rules 9001), in order to evaluate the solid stability of the crystal form A of compound of formula (I), the stability of the crystal form A was investigated under the influencing factors (high temperature, high humidity and light), 60°C / 75%RH and 40°C / 75%RH conditions. The crystal form A was placed under high temperature (60°C, closed) and high humidity (92.5%RH, sealed film wrapped and pierced with 5 small holes) conditions for 1 week and 2 weeks respectively, and was placed under ICH conditions (total visible light illumination reached 1200000Lux·hrs, total ultraviolet light illumination reached 200W·hrs / m 2 The samples were placed under visible and UV light (the light-shielded control sample was also placed and wrapped in tin foil) at 60°C / 75% RH (wrapped in Parafilm and punctured with five small holes) for 1 and 2 months, and at 40°C / 75% RH (wrapped in Parafilm and punctured with five small holes) for 1, 2, and 3 months. XRPD analysis was performed on all stability samples to detect changes in crystal form. The results are shown in Table 19.

[0293] Accurately weigh approximately 10 mg of the crystalline form and place it in a dry, clean glass vial. Spread it into a thin layer, cover with aluminum foil, poke a small hole, and place it under influencing test conditions and accelerated conditions. Samples placed under illumination (visible light 1200000 Lux, UV 200W) were placed in a transparent glass vial, fully exposed. Samples for XRPD analysis were placed separately.

[0294] After the samples were removed at the time point, they were capped, sealed with parafilm, and stored in a -20°C refrigerator. For sample preparation, the samples were removed from the refrigerator, returned to room temperature, and 10 mL of 80% ACN was added. The sample was sonicated for 2 minutes to dissolve, resulting in a solution with a concentration of approximately 1 mg / mL. Liquid chromatography was used for sample injection analysis, and the test results were compared with the initial test results on day 0. The test results are shown in Table 19 below.

[0295] Preparation of Day 0 standard solution: Weigh approximately 10 mg of the crystalline form into a 10 mL volumetric flask, dissolve it in 80% acetonitrile and dilute to the mark.

[0296] At the same time, HPLC tests were performed on all stability samples, and the specific results are summarized in Table 19.

[0297] Table 19 Solid stability test results of compound A of formula (I)

[0298]

[0299] Conclusion: The purity and crystal form of the compound A of formula (I) did not change significantly under all stability conditions (high temperature, high humidity, and light), and it has good chemical stability.

[0300] Activity test

[0301] 1. In vitro evaluation of Syk protein kinase inhibitory activity

[0302] Experimental purpose: To detect the Syk protein kinase inhibition IC of the compound 50 value.

[0303] Experimental materials: Syk kinase (Invitrogen, PV3857)

[0304] DTT (Sigma#43815): dithiothreitol

[0305] ATP (Sigma#A7699): Adenosine triphosphate

[0306] MgCl2 (Sigma #63020): Magnesium chloride

[0307] MnCl2 (Sigma#M1787): Manganese chloride

[0308] EDTA (Invitrogen #15575-020): Ethylenediaminetetraacetic acid

[0309] HEPES Buffer (Invitrogen #15630-080): Zwitterionic sulfonic acid buffer

[0310] KinEASE TM TK (Cisbio #62TK0PEC, 20000 tests): HTRF kinase kit

[0311] Low volume,384-well,white polystyrene plate(Greiner#784075)

[0312] 384 Well Microplates (Greiner#781946): 384 well plates

[0313] Centrifuge (Eppendorf #5810R)

[0314] Pipette (Eppendorf)

[0315] Greiner pipette

[0316] Pipette (Eppendorf)

[0317] Mutidorp pipette

[0318] POD 810 Plate Assembler fully automated microplate pretreatment system

[0319] Envision Reader: Plate Reader

[0320] Experimental steps and methods:

[0321] a) Compound dilution and plate making

[0322] 1) Weigh the compound powder and dissolve it in a certain amount of DMSO to an initial concentration of 10 mM.

[0323] 2) Dilute the compound to 0.74 mM and plate using POD18, 135 nL per well, with a starting compound concentration of 10 μM, 11 concentration points, and a 3-fold decreasing gradient dilution.

[0324] b) Enzyme and substrate reaction stage

[0325] 1) Prepare the experimental buffer by diluting the 5× HTRF Buffer in the kit to 1× HTRF Buffer and adding the specified amount of DTT and MgCl2 solution.

[0326] 2) Prepare SYK enzyme reaction solution with 1× HTRF Buffer to a final SYK kinase concentration of 0.0156 ng / μL.

[0327] 3) Prepare a TK-Substrate-biotin / ATP mixture so that the final substrate concentration is controlled at 0.2 μM and the ATP concentration is controlled at 2 μM.

[0328] 4) Use a Mutidorp pipette to add samples, add 5 μL of SYK enzyme solution and TK-Substrate-biotin / ATP mixture to each well, and incubate at 23°C for 1 hour.

[0329] c) Detection stage:

[0330] 1) Add 13.33 mL of EDTA solution to the kit's detection buffer, and add the specified amount of Eu-labeled antibody and XL-665 to prepare the detection solution.

[0331] 2) Use a Mutidorp pipette to add 10 μL of detection solution to each well and incubate at 23°C for 1 hour to terminate the reaction of the enzyme and substrate mixture.

[0332] 3) After centrifugation, read the value on Envision.

[0333] d) Data analysis: XL-Fit was used to analyze the data and calculate the IC value of the compound. 50 The results are shown in Table 20.

[0334] Experimental results:

[0335] Table 20 Syk inhibitory activity test results

[0336] Compound <![CDATA[IC of Syk 50 (nM) <!-- 24 -->]]> Formula (I) Compound A Crystalline Form 25

[0337] Conclusion: Crystal form A of compound of formula (I) has good inhibitory activity against Syk.

[0338] 2. In vitro evaluation of KDR (VEGFR-2) protein kinase inhibitory activity

[0339] Purpose of the experiment

[0340] The KDR Kinase Assay Kit is designed to be used As a detection reagent to measure KDR kinase activity, the IC 50 The values were used as indicators for compound screening and analysis.

[0341] Experimental methods and steps

[0342] ADP-GLO TM The kinase assay is a luminescent kinase assay that measures the formation of adenosine diphosphate (ATP) by kinases; ADP is converted to ATP by SuperGlo TM Luciferase converts the luminescence signal into a light signal. The luminescence signal is positively correlated with the amount of ADP and the kinase activity. This assay is well suited for measuring compound activity, making it ideal for preliminary screening and kinase selectivity analysis. ADP-Glo TM Kinase assays can be used to monitor the activity of nearly any ADP-generating enzyme (e.g., kinase or ATPase):

[0343] 1) Dilute enzyme, substrate, ATP, and inhibitor in kinase buffer;

[0344] 2) 384-well plate: 1 μL inhibitor or (5% dimethyl sulfoxide solution), 2 μL KDR enzyme, 2 μL substrate / ATP mixture;

[0345] 3) Incubate at room temperature for 60 minutes;

[0346] 4) Add 5 μL ADP-GLO TM Reagents;

[0347] 5) Incubate at room temperature for 40 minutes;

[0348] 6) Add 10 μL of kinase detection reagent;

[0349] 7) Incubate at room temperature for 30 minutes;

[0350] 8) Record luminescence (integration time 0.5-1 s). Data are displayed as relative light units (RLU), which directly correlates to the amount of ATP produced. Correlate the percentage of ATP converted to ADP per kinase amount with the corresponding signal-to-background ratio.

[0351] 9) Data analysis: (a) Titration of KDR enzyme with 50 μM ATP to show the luminescent signal generated by KDR enzyme; (b) Staurosporine dose response was generated using 1.5 ng of KDR to determine the inhibitor IC 50 The results are shown in Table 21.

[0352] Experimental results

[0353] Table 21 KDR inhibitory activity test results

[0354] Compound <![CDATA[IC for KDR 50 (nM)]]> Formula (I) Compound A Crystalline Form 28

[0355] Conclusion: Crystal form A of compound of formula (I) has good inhibitory activity against KDR (VEGFR-2).

[0356] 3. Pharmacokinetic evaluation

[0357] Experimental purpose: To study the pharmacokinetics of the compound in ocular tissues after a single eye drop administration in male SD rats

[0358] Experimental materials: SD rats (male, 7-10 weeks old, WTLH / SLAC)

[0359] Experimental Procedure: In this study, 18 male SD rats were provided by Beijing Weitonglihua Experimental Animal Technology Co., Ltd. and randomly divided into 6 groups (3 / group). Each group of animals received a single ophthalmic administration of 0.730 μM (5 mg / mL) OT202 eye drops (30 μL / eye). All animals were not fasted before administration. The details of the administration and blood collection of the crystalline form of compound A of formula (I) are shown in Tables 22 and 23 below, respectively.

[0360] Table 22 Single eye drop administration parameters for male SD rats

[0361]

[0362] Table 23 Blood sampling protocol after single eye drop administration in male SD rats

[0363] Group Animal No. matrix Sampling time point (h) 01 R01, R02, R03 Plasma, conjunctiva, aqueous humor, cornea, upper and lower eyelids 0.5 02 R04, R05, R06 Plasma, conjunctiva, aqueous humor, cornea, upper and lower eyelids 1 03 R07, R08, R09 Plasma, conjunctiva, aqueous humor, cornea, upper and lower eyelids 3 04 R10, R11, R12 Plasma, conjunctiva, aqueous humor, cornea, upper and lower eyelids 6 05 R13, R14, R15 Plasma, conjunctiva, aqueous humor, cornea, upper and lower eyelids 12 06 R16, R17, R18 Plasma, conjunctiva, aqueous humor, cornea, upper and lower eyelids 24

[0364] The pharmacokinetic parameters of the crystal form A of the compound of formula (I) in SD rats are shown in Table 24 below.

[0365] Table 24 Pharmacokinetic test results

[0366]

[0367]

[0368] C max : maximum concentration; T max : Time when concentration reaches peak; T 1 / 2 : elimination half-life; T last : time of last measurable concentration; AUC 0-last : Area under the plasma concentration-time curve from time 0 to the last quantifiable time point; AUC 0-inf : area under the plasma concentration-time curve from time 0 to extrapolation to infinity; MRT 0-last : Mean residence time from time 0 to the last quantifiable time point; MRT 0-inf : average residence time from time 0 to extrapolation to infinity; AUC ratio: tissue AUC 0-last / Plasma AUC 0-last .

[0369] *: The linear regression coefficient of the drug concentration elimination phase is less than 0.9.

[0370] --:not applicable.

[0371] Conclusion: The crystal form A of compound of formula (I) has good pharmacokinetic properties, including good eye-to-blood ratio and tissue exposure.

Claims

1. Crystal form A of the compound of formula (I), characterized in that Its Cu Kα radiation X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 16.76±0.20°, 17.55±0.20°, 21.84±0.20°, 2. The crystal form A according to claim 1, wherein its X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 15.36±0.20°, 16.76±0.20°, 17.55±0.20°, 21.84±0.20°, 23.49±0.20°, and 24.42±0.20°.

3. The crystal form A according to claim 2, wherein its X-ray powder diffraction pattern using Cu Kα radiation has characteristic diffraction peaks at the following 2θ angles: 11.96±0.20°, 14.14±0.20°, 15.36±0.20°, 16.76±0.20°, 17.55±0.20°, 21.25±0.20°, 21.84±0.20°, 23.49±0.20°, 24.42±0.20°, 28.37±0.20°, and 30.15±0.20°.

4. The crystal form A according to claim 3, whose XRPD pattern is shown in Figure 1. The crystal form A according to any one of claims 1 to 4, wherein the differential scanning calorimetry curve thereof has an endothermic peak at 332.4°C±3°C.

6. The crystal form A according to claim 5, whose DSC spectrum is shown in Figure 2.

7. The crystal form A according to any one of claims 1 to 4, wherein the thermogravimetric analysis curve thereof shows a weight loss of 2.41±0.20% at 250.0°C±3°C.

8. The crystal form A according to claim 7, whose TGA spectrum is shown in Figure 3.

9. Use of the crystal form A according to any one of claims 1 to 8 in the preparation of a medicament for treating allergic diseases, autoimmune diseases or inflammatory diseases.

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